Increasing numbers of hepatitis C (HCV) transmissions are being observed in high-risk groups including young people who inject drugs (PWID) and HIV positive men who have sex with men (MSM) causing major international concern. Novel highly effective oral directly acting antiviral (DAA) drugs promise hope for the treatment of HCV at an individual and population level, yet major barriers and uncertainty exist regarding their use in marginalised groups. Early engagement, testing and treating these populations, has significant potential to limit HCV transmission and ongoing epidemics, yet the importance of adherence, risk behaviour change and the potential for subsequent reinfection in the era of interferon free treatments are currently poorly understood. In prior NIH funded projects using interferon-based therapies, over 200 PWID/HIV positive MSM with recent HCV were engaged and treated demonstrating the feasibility, safety and efficacy of treatment in these high risk groups. In this proposed project a unique international collaboration of investigators (termed the REcently ACquired HCV Trials (REACT) network) is utilised to address critical current questions. A randomised clinical trial involving 250 HIV positive and negative subjects with recent HCV will be performed to evaluate the effectiveness of short (6 week) course therapy versus standard (12 week) course therapy with the DAA combination sofosbuvir/GS5816. During therapy novel methods of adherence monitoring including electronic blister packs and therapeutic drug monitoring will be used to assess adherence to treatment and its impact on treatment outcome. Subjects will be followed for up to 2 years post treatment allowing the most extensive evaluation of reinfection incidence post treatment in individuals with recent HCV and in-depth evaluation through behavioural questionnaires of the impact of engagement and treatment at this stage on risk reduction and drug and sexual practice change. All analyses will be examined in both HIV positive and negative groups. Serum and cells will be stored throughout to allow assessment of immunological responses to HCV following DAA treatment within the first year of infection and to gain unique insights into the immune response surrounding HCV clearance and reinfection. These specimens will also expand extensive storage banks from subjects with recent HCV treated in the interferon-era enhancing a valuable resource. Findings from this project will provide recommendations to guide clinicians and public health policy in the effective management of HIV positive and negative individuals and populations at risk for, or recently infected with HCV.